This invention relates generally to materials which are resistant to in vivo calcification, and more particularly, to calcification-resistant biomaterials, suitable for implantation in a living being, comprising a synthetic biocompatible polymer to which an anticalcification agent(s) is bound by stable, irreversible covalent bonds.
More than 100,000 cardiac valve prostheses are placed in patients each year. Frequently, valve replacement surgery is the only means of treating cardiac valve disease. Currently used replacement valves include mechanical valves which may be composed entirely of a synthetic polymeric material such as polyurethane; bioprosthetic valves derived from bovine pericardium or porcine aortic valves; and aortic homografts.
Use of mechanical valves is frequently complicated by thrombosis and tissue overgrowth leading to valvular failure. Calcification is the most frequent cause of the clinical failure of bioprosthetic heart valves fabricated from porcine aortic valves or bovine pericardium. Human aortic homograft implants have also been observed to undergo pathologic calcification involving both the valvular tissue as well as the adjacent aortic wall albeit at a slower rate than the bioprosthetic heart valves. Pathologic calcification leading to valvular failure, in such forms as stenosis and/or regurgitation, necessitates re-implantation. Therefore, the use of bioprosthetic heart valves and homografts has been limited because such tissue is subject to calcification.
Pathologic calcification also further complicates the use of synthetic vascular grafts and other artificial heart devices, such as ventricular assist systems, because its affects the flexibility of the synthetic polymers used to produce the devices.
The mechanism for pathological calcification of cardiovascular tissue is not understood. Generally, the term "pathologic calcification" refers to the deposition of calcium phosphate mineral salts in association with a disease process. Calcification may be due to host factors, implant factors, and extraneous factors, such as mechanical stress. There is some evidence to suggest that deposits of calcium are related to devitalized cells, and in particular, cell membranes, where the calcium pump (Ca.sup.+2 -Mg.sup.+2 -ATPase) responsible for maintaining low intracellular calcium levels is no longer functioning or is malfunctioning. Calcification has been observed to begin with an accumulation of calcium and phosphorous, present as hydroxyapatite, which develops into nodules which can eventually lead to valvular failure.
Research on the inhibition of calcification of bioprosthetic tissue has focussed on tissue pretreatment with either detergents or diphosphonates. Both of the aforementioned compounds tend to wash out of the bioprosthetic tissue with time due to blood-material interactions. Thus, these treatments merely delay the onset of the inevitable calcification process. To date, long-term prevention of calcification has been an unattainable result. Accordingly, there is a need for a means of providing long-term calcification resistance for bioprosthetic or synthetic heart valves and other implantable, or in-dwelling, devices which are subject to in vivo pathologic calcification.
Systemic use of anticalcification agents, such as diphosphonates, results in significant side effects on bone, and overall, growth. Site specific therapy offers treatment with low regional drug levels and minimal side effects.
It is, therefore, an object of this invention to provide biomaterials for implantation in a mammal which have increased resistance to in vivo pathologic calcification.
It is another object of this invention to provide biomaterials for implantation in a mammal which have a long-term, or prolonged, resistance to in vivo pathologic calcification.
It is also an object of this invention to provide biomaterials for implantation in a mammal which have localized calcification inhibition and, hence, avoid the toxic side effects associated with systemic administration of anticalcification agents.
It is a further object of this invention to provide new synthetic biomaterial elastomers with increased utility due to retention of flexibility over an extended period of time.
It is additionally an object of this invention to provide a method of fabricating and/or treating biomaterials for implantation in a mammal to render the biomaterials resistant to in vivo pathologic calcification.
It is yet a further object of this invention to provide a novel method of covalently bonding anticalcification agents, specifically polyphosphonates or other anticalcification agents bearing functionalities capable of epoxide derivatization, to biomaterials.
It is also another object of this invention to provide a novel method of irreversibly binding polyphosphonates to synthetic biomaterials for permanent calcification inhibition.